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Keywords:

  • comparative oncology;
  • lymphoscintigraphy;
  • metastasis;
  • sentinel lymph node;
  • surgical oncology

Abstract

  1. Top of page
  2. Abstract
  3. Sentinel lymph node principles
  4. The case for SLN in veterinary oncology
  5. Sentinel lymph node evaluation
  6. SLN mapping techniques
  7. Conclusion and future directions
  8. References

Being the first lymph node or nodes to which many primary tumours reliably drain, the disease status of the sentinel lymph node/s (SLN) is important in the prediction of survival. SLN identification and biopsy are critical in the staging of human cancers. The status of the SLN helps determine prognosis and shape treatment plans. SLN evaluation is currently not routinely performed in veterinary oncology, not even at specialty oncology practices. Given the prognostic importance of lymph node involvement in tumours such as mammary gland carcinoma, osteosarcoma, synovial cell sarcoma and mast cell tumours, SLN evaluation should be incorporated into routine clinical practice so as to improve our clinical assessment of veterinary oncologic patients.


Sentinel lymph node principles

  1. Top of page
  2. Abstract
  3. Sentinel lymph node principles
  4. The case for SLN in veterinary oncology
  5. Sentinel lymph node evaluation
  6. SLN mapping techniques
  7. Conclusion and future directions
  8. References

The use of sentinel lymph node (SLN) biopsy to assess the regional lymphatic basin in cases of breast cancer1 and melanoma2 has become the standard of care in human oncology. The SLN is defined as the first lymph node (or nodes) within a lymphatic drainage basin to which a primary tumour reliably drains. Hence the presence or absence of tumour cells in the SLN is predictive of lymphatic spread of the tumour, and histopathologic analysis of these ‘SLNs’ is considered to reflect the disease status of the entire lymphatic field in human, and where applicable, veterinary medicine.

The concept of lymphatic mapping and SLN biopsy was first described in cases of penile cancer,3 where it was found that the status of the SLN predicted survival. Similar findings were subsequently described in cases of melanoma.4 Lymphoscintigraphy, the injection of a radioactive tracer at the tumour site to identify lymphatic drainage, and intratumoral/peritumoural blue dye injection have been used either separately or more commonly in combination to locate the SLN in tumours such as breast carcinomas and cutaneous melanomas for staging and therapeutic purposes. If the SLN contains metastatic cells, surgical excision of the nodal basin can be performed at another subsequent surgical procedure if the resultant improvement in prognosis outweighs the morbidities. If the SLN is negative for metastasis, the assumption may be made that the rest of the regional nodes are likely free from disease, and surgical excision of the nodes is unnecessary, thus sparing the patient the associated morbidities of lymph node dissection.

Methods such as lymphoscintigraphy for SLN identification and subsequent biopsy of the affected node/s to stage the regional lymphatic basin have modified the prescription for radical lymphadenectomy in breast cancer patients, a procedure that carries complications such as pain, numbness, lymphoedema, lymphangitis and reduced range of arm motion.5 Biopsy of the SLN allows identification of node-negative patients, sparing them from a radical lymphadenectomy that benefits them little.6 In melanoma patients, SLN involvement is one of the most important prognostic factors,7 and accurate identification of SLNs has improved tumour staging so that only the node-positive patients need to undergo complete regional lymph node dissection. The issue of incorrect nodal basin dissection that particularly plagued the management of cutaneous melanoma patients without palpable lymphadenopathy has also been minimized with the use of lymphoscintigraphy to accurately identify the affected lymph node.6 Given the potential advantages of SLN biopsy, its use has been explored for malignancies other than breast cancer and melanoma. These include colon cancer,8,9 squamous cell carcinoma of the head and neck,10,11 gynaecologic cancers,12–14 thyroid cancer,15,16 Merkel cell carcinoma,17–19 upper gastrointestinal cancers20,21 and non–small cell lung cancer.22 Sentinel node biopsy is increasingly being used for staging and detection of occult micrometastases. Micrometastasis refers to the systemic spread of small numbers of tumour cells too few to be detected by screening tests and is thought to be largely responsible for metastatic disease in patients originally diagnosed as node negative. False negatives can still occur with sentinel node biopsies. For example, axillary sentinel node biopsies carry a false negative rate of 5–15%.23,24 In spite of this, axillary sentinel node evaluation has become increasingly indispensable in the staging and management of breast cancer,24,25 since the procedure carries satisfactory sensitivity that can be additionally improved by refining parameters such as the number of SLNs removed.24 Therefore, general SLN principles such as the targeted approach of sampling only the relevant nodes together with the high sensitivity of SLN evaluation make it a superior clinical tool that should be incorporated into veterinary oncology.

The case for SLN in veterinary oncology

  1. Top of page
  2. Abstract
  3. Sentinel lymph node principles
  4. The case for SLN in veterinary oncology
  5. Sentinel lymph node evaluation
  6. SLN mapping techniques
  7. Conclusion and future directions
  8. References

There is a paucity of data in the veterinary literature that address the issue of SLN identification and biopsy (Table 1). The most likely reasons for this are the lack of basic studies looking at lymph drainage patterns, an underappreciation of the clinical importance of positive lymph nodes, the high morbidity associated with removal of local lymph nodes whose location is not accurately identified and the specialized equipment and training required to reliably identify and remove SLNs. Given the success of these techniques in human oncology, an evaluation of advanced techniques for the identification and biopsy of SLNs in veterinary oncology patients is warranted. The indications and usefulness of these modalities in veterinary oncology patients are yet to be proven; however, the minimally invasive nature of the techniques and the large impact that a positive lymph node has on the prognosis in some disease processes may make it invaluable in the staging of our cancer patients. Herring et al.26 conducted a retrospective study evaluating the importance of lymph node staging in oral and maxillofacial tumours in dogs and cats. The study concluded that since metastases occur in lymph nodes other than the routinely assessed mandibular lymph node, routine staging should also include excisional biopsies of the parotid and medial retropharyngeal lymph nodes for histopathologic evaluation.

Table 1.  Reported instances of sentinel lymph node (SLN) identification in veterinary medicine, highlighting the paucity of data
Tumor typeMethod
Canine head and neck tumours31Contrast-assisted ultrasound
Oral melanoma (ongoing study)Lymphoscintigraphy/new methylene blue dye
Forelimb osteosarcoma (ongoing study)Lymphoscintigraphy/new methylene blue dye

In veterinary clinical practice, well-established guidelines for SLN evaluation are lacking. Lymph nodes are generally aspirated or biopsied only if palpably enlarged, leading to inaccurate disease staging. A study demonstrated that the relationship between lymph node size and lymph node metastasis is not reliable enough for accurate clinical staging of dogs with melanoma.27 Thus, although methods for evaluating the regional lymph node such as fine-needle aspiration or biopsies can have 100 and 64% sensitivity respectively,28 the absence of a targeted evaluation of the SLN compromises staging accuracy. Some practitioners have chosen to routinely excise the entire local lymph node during removal of the primary tumour so as to minimize the incidence of falsely negative nodes diagnosed by cytology or incisional biopsy. However, SLN evaluation provides a more focussed technique that eliminates the need for prophylactic removal of a potentially unaffected node. Doppler spectral analysis has also been described as a noninvasive ultrasonographic method of distinguishing between neoplastic and inflammatory canine lymph nodes,29 but the study only utilized dogs with enlarged superficial lymph nodes, which again lacks the specific targeting of SLNs for evaluation. However, Doppler spectral analysis potentially could be incorporated into SLN evaluation to provide an initial assessment of nodal metastasis, once the SLNs have been accurately identified.

As with human cancer patients,2,6,30 the consistent identification of veterinary patients in which regional lymph node evaluation should be a routine procedure is required before adopting these SLN evaluation techniques into general veterinary oncology. Lurie et al.31 examined the use of contrast-assisted ultrasound detection of SLNs in dogs with head and neck tumours. The study reinforced the difference between human and canine lymphatic drainage of the head and neck, and showed that contrast-assisted ultrasound can be used either as a single modality or as an adjunct to lymphoscintigraphy to detect SLNs. The differences in lymphatic anatomy between humans and animals validate the need to establish veterinary-specific SLN identification, as we cannot extrapolate human SLN data directly to our animal patients.

Lymph node involvement in veterinary patients has been shown to be a strong prognostic factor in mammary gland tumour,32,33 malignant melanoma,34 osteosarcoma,35,36 primary lung carcinoma,37,38 synovial cell sarcoma39 and mast cell tumour,40 among others. There is a wealth of literature describing the benefits of using various techniques of SLN identification and biopsy in human breast cancer and malignant melanoma patients.41–44 Thus, a clear indication exists for the adaptation of these techniques for use in veterinary patients for which the information is most clinically relevant.

Malignant melanoma in dogs is an aggressive tumour that metastasizes first to regional lymph nodes and then to distant sites.45,46 Staging and prognosis of the disease is dependent on knowledge of the lymph node status.34 In a lymph drainage study of the mouth and tongue conducted by one of the authors (unpublished data: Milgram, J: personal communication), the drainage pattern of methylene blue dye from the cranial and caudal aspects of the mouth was evaluated (Fig. 1, unpublished data). Only one veterinary clinical study has been undertaken to evaluate SLN identification, biopsy and excision in cases of melanoma,31 even though targeted assessment of the SLN improves the accuracy of clinical staging. The inadequacy of only sampling the most accessible lymph nodes is illustrated by the retrospective study of oral and maxillofacial tumours which included canine melanoma—the authors concluded that investigating the status of all regional lymph nodes will improve detection of metastatic disease compared to only sampling the mandibular lymph node.26

image

Figure 1. Methylene blue drainage from mouth and lip in malignant melanoma.

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Evaluation of the regional lymph nodes is one of the critical requirements in staging mammary gland tumours and the lymph drainage pattern from the mammary glands in dogs has been described.47–49 Intra-operative decision making is based on ease of access and presence of a palpably enlarged lymph node. As a result of this, the inguinal lymph node is generally removed if the fifth mammary gland is removed while the axillary lymph node, which may consist of multiple nodes, is rarely evaluated unless palpable due to potential morbidity associated with extirpation to the brachial plexus and axillary artery and vein. Disease-free interval is reported to be shorter in mammary tumour patients which are node positive, with 80% of these dogs experiencing tumour recurrence within 6 months.50–52 Another study reported the 2-year survival rate of canine malignant mammary tumours to be significantly lower for patients with regional and/or distant lymph node metastasis than for those without lymph node involvement.32 Since lymph node status has such a large impact in a variety of veterinary neoplasms, more thorough investigation of the SLN is warranted.

Regional lymph node metastasis in canine osteosarcoma, due to its low incidence, has not been extensively studied.36 A retrospective study found that both median disease-free interval and survival time were significantly longer in dogs with appendicular osteosarcoma without lymph node involvement versus dogs with histologic evidence of lymph node metastasis. Dogs without lymph node involvement had a median disease-free interval of 238 days and a median survival time of 318 days compared with 48 and 59 days, respectively for dogs with positive nodes.36 In a lymph drainage study of the canine forelimb (unpublished data: Milgram, J: personal communication), it was found that drainage of methylene blue injected peritumourally occurred inconsistently both laterally and medially on the limb, which supports the need for further evaluation of SLN drainage in this anatomic location. Based on this preliminary data that suggests that lymphatic drainage may occur to more than one nodal bed, the above-referenced study36 evaluating incidence of lymph node metastasis in osteosarcoma patients may have underestimated its frequency, since only the axillary lymph node was evaluated. Although osteosarcoma uncommonly metastasizes to the local lymph node, the impact on prognosis of a positive node may justify a more thorough evaluation of SLNs. A clinical study is currently underway to evaluate lymph node basins of the forelimb in an effort to establish pattern of SLN drainage.

In short, it behooves the practising veterinarian to understand the importance of SLN evaluation in oncologic disease management—it improves staging accuracy by assessing the relevant lymph nodes for metastatic disease and reduces patient morbidity by eliminating potentially unnecessary prophylactic surgical removal of the entire regional lymph node.

Sentinel lymph node evaluation

  1. Top of page
  2. Abstract
  3. Sentinel lymph node principles
  4. The case for SLN in veterinary oncology
  5. Sentinel lymph node evaluation
  6. SLN mapping techniques
  7. Conclusion and future directions
  8. References

The number of methods available for regional lymph node evaluation in veterinary patients has increased in parallel with the increasingly sophisticated imaging techniques available. There are limitations to each of the techniques—fine-needle aspiration, excisional and needle core biopsies require lymph node identification and accessibility. Palpation has been evaluated as a sole technique for the identification of lymph node involvement and was found to be an extremely inaccurate predictor of nodal metastasis in both humans and animals.27,28,53 This emphasizes the point that sampling only enlarged lymph nodes does not provide optimal clinical staging. The current gold standard for determining lymph node metastasis is histopathologic examination of the resected node.54 Serial section and assessment of the lymph nodes performed by the preparation and evaluation of multiple sections of an affected lymph node increase the likelihood of detecting positive lymph nodes.26,55

A novel reverse-transcriptase polymerase chain reaction assay, the Breast Lymph Node (BLN) Assay, to detect SLN metastasis greater than 0.2 mm has been developed for human breast cancer patients. The BLN Assay is reported to have high sensitivity and specificity, and decreases the incidence of false negatives by sampling 50% of the lymph node. When used in conjunction with histologic assessment of the SLN, the BLN Assay reportedly improves accuracy of detecting metastases.56

The subcapsular portion of the lymph node is a common site of early metastasis to the SLN.57 Lymph drainage occurs in an orderly manner via afferent lymphatic vessels into these subcapsular sinuses, which can be identified, marked and evaluated. Carbon particles may be injected together with a blue dye used in SLN identification because they accumulate in the subcapsular sinus, thus highlighting the likely areas of micrometastasis when evaluated histopathologically. The pattern of carbon accumulation also aids in the location of melanoma cells within the lymph node. Using this technique, early lymph node metastasis has been detected in human melanoma patients.58,59

A potential method of identifying node–positive breast cancer and melanoma patients is via analysis of cytokine secretion by the SLNs. Patients without metastatic disease can have higher secretion of cytokines such as interleukin (IL)-2, IL-10, interferon γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to patients with lymph node metastasis.60,61

Whether the therapeutic benefit of eliminating a potential metastatic site outweighs the morbidities that accompany nondiscriminating surgical excision of all nodal basins remains a much debated issue.54,62 Hence there should be more active investigations in veterinary medicine to keep pace with human medical advances in development of methods to increase the accuracy of SLN identification and evaluation so as to better target our diagnostic and prognostic capabilities while minimizing patient morbidity. Preoperative and/or intra-operative lymphatic mapping, although technically difficult, has the potential to accurately identify SLNs and allows biopsy only of those selected nodes.

SLN mapping techniques

  1. Top of page
  2. Abstract
  3. Sentinel lymph node principles
  4. The case for SLN in veterinary oncology
  5. Sentinel lymph node evaluation
  6. SLN mapping techniques
  7. Conclusion and future directions
  8. References

A common modality for lymphatic mapping in human oncology is the preoperative use of a radiolabelled colloid with a gamma camera to identify the SLN, followed by intra-operative identification of the ‘hot’ (aka radioactive) lymph node using a hand-held gamma probe.41 Injection of a blue dye peritumourally is used to further assist in the identification of the SLN. Lymph nodes that take up both radiolabelled colloid and blue dye are referred to as ‘hot and blue’.41,43 A limited number of papers using similar techniques have been reported in animals.63–67 Use of single agent visible dyes was first described in a feline model of dermal lymphatic drainage, where various mapping dyes were injected intradermally to facilitate SLN identification. In this study, isosulfan blue proved to be most efficacious.67 A study in dogs has identified the SLN of the lungs by intralobar injections of technetium sulfur colloid and isosulfan blue. In this study, a hand-held gamma probe as well as direct observation enabled pulmonary lymphatic mapping.65 The use of other imaging modalities such as the sonographic evaluation of lymph nodes and ultrasound-assisted identification of the SLN are emerging techniques in veterinary medicine.31,68 Lurie et al. have reported the use of a microbubble contrast medium injected peritumourally in a quadrant pattern to enable sonographic identification of the SLN.31 This technique has potential for facilities not licensed for nuclear medicine.

Near-infrared (NIR) fluorescent quantum dots (QDs) have been used in animals for SLN mapping. The NIR QDs injected into tissue are cleared by the lymphatic system and may be visualized intra-operatively using NIR fluorescence imaging systems. This technique allows the real time mapping of lymphatic flow and the identification of the SLN. These NIR QDs have been used to map the lymphatic drainage and the SLN of skin,42 oesophagus,69 lung,70 gastrointestinal tract,71 as well as the pleural72 and peritoneal spaces,73 lower limb and mammary tissue.74 NIR fluorescent albumin and QDs have been used to detect SLN in invasive transitional cell carcinoma in dogs. A NIR lymphatic tracer was injected into the wall of the urinary bladder using a quadrant pattern and the lymphatic drainage and SLN were identified using dedicated NIR equipment.75

There is currently no gold standard established for SLN identification in veterinary medicine, and the precision of the identification depends largely on the method used and the expertise of the surgeon performing the procedure.30 A human multicenter trial of SLN biopsy showed that surgeons need to perform an average of 50 procedures before becoming clinically competent.76

Conclusion and future directions

  1. Top of page
  2. Abstract
  3. Sentinel lymph node principles
  4. The case for SLN in veterinary oncology
  5. Sentinel lymph node evaluation
  6. SLN mapping techniques
  7. Conclusion and future directions
  8. References

Assumptions of lymphatic drainage basins based solely on proximity of location to the primary tumour are not always correct.77,78 In addition, the possibility that a single location may drain via multiple lymph node basins is distinct.31 Hence, the importance of identifying and biopsying every SLN cannot be overemphasized—the SLN is a reliably sensitive and specific indicator of the actual extent of metastatic disease in a patient.79,80 Its assessment increases accuracy in patient staging, thus ensuring that patients who may have been staged without nodal involvement in the absence of proper SLN evaluation will now receive the benefit of appropriate therapy. Reports in human oncology showed that micrometastasis was detected in as high as 30% of patients who originally were staged as node negative without SLN evaluation, and that these patients benefited from a subsequent change in treatment plan.80–82 The development of molecular assays such as the BLN Assay for SLN metastasis detection will continue to improve our accuracy in SLN evaluation and thus treatment planning.

The evaluation of state of the art techniques for SLN identification in veterinary medicine has been initiated at Colorado State University's Animal Cancer Center as well as other large referral centers. Oral malignant melanoma and forelimb osteosarcoma patients are currently being recruited to a pilot study in which a combination of 99mTc-labelled nucleotide and peritumoural injections of methylene blue dye are being used to facilitate SLN localization (Fig. 2).

image

Figure 2. Lymphoscintigraphy using gamma camera and probe.

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Given that the SLN is the most likely site for initial regional metastasis and that its accurate identification and evaluation will provide invaluable prognostic and diagnostic information crucial for optimal treatment planning, more attention should be devoted to the inclusion of SLN evaluation when staging the tumours of our veterinary patients. Proper SLN mapping with lymphoscintigraphy and blue dye injections will also guide the surgeon in removing only the necessary lymph nodes, thereby improving the speed and accuracy of lymph node dissection.

References

  1. Top of page
  2. Abstract
  3. Sentinel lymph node principles
  4. The case for SLN in veterinary oncology
  5. Sentinel lymph node evaluation
  6. SLN mapping techniques
  7. Conclusion and future directions
  8. References
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